MADRIGAL PHARMACEUTICALS, INC. — Call Transcript 2026

All right, let's get started. Oh, nice full room here. Welcome everyone to the Madrigal Fireside Chat at the 46th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral. With us here from Madrigal, in order, is Bill Sibold, CEO, David Soergel, CMO, and Mardi Dier, CFO. Welcome everyone. Thank you for being here. Maybe let's start with revenue growth, and company goals. We came off another great earnings report. The launch is going exceptionally well, and at the same time you did 3 BD deals in about six months, like within, I don't know, 14 months of Dave joining, to build the pipeline. Before we get into the questions, maybe Bill, can you just give a brief, like three-minute update on the strategy and performance so far this year? Yeah. Ritu, first of all, thanks for having us. It's always a great moment of the year to be here. As you said, things are going just great. Taking a look at Rezdiffra, off to a strong start in its Q7 of launch, annualizing at $1.3 billion. Market growing at about 50% over two years. Because of the current performance and what we anticipate for the future with the market growth and just with continued penetration- 50% is diagnosed patients? 50% diagnosed patients at the treating physicians that we are calling on. Oh, okay. Because of those favorable dynamics, we've gone to start building a pipeline. When you look specifically at 2025, hard to imagine really a better year. As I said, we end up annualizing at over $1 billion- Mm-hmm. Close to $1 billion in sales for 2025. Over 36,250 patients on therapy. As we finish the year, we exit, as we talk about this 50% growth in the market. Mm-hmm. We've started to build a pipeline I'll get to in a minute. Yep We've also secured 2045 IP for Rezdiffra. We've really put ourselves in a position for long-term growth. The way we thought about the pipeline really is Rezdiffra is a great product. It's a foundational product. It's become quickly the standard of care. How do you make a better product even? Mm-hmm. How do we get a better response in the overall population, or how do we identify a subgroup of patients that may respond better? It's such a foundational therapy when you look across all subgroups, subpopulations, the effect is pretty much the same. As we add new mechanisms of action, as you said, in the last six months, we've gone from a company that has a single product in the pipeline to a company that now has over 10 products in the pipeline. Yeah. The idea is we will look at combination therapy with Rezdiffra to see if we can get a better response for the whole population or a subgroup and take that forward fast, otherwise kill it fast. Mm-hmm. We started with an oral GLP-1. We think that mechanistically makes a lot of sense because we know from our trials that just with over 5% weight loss, we can get a better effect with Rezdiffra. We did the DGAT2 with Pfizer. We think mechanistically makes a lot of sense. Maybe we'll talk about that a little bit later. Yep. siRNA, we did six programs that we have brought in that we are directing towards MASH as well. We like it. It's liver-directed therapy as well, and think that there's good rationale for combination with Rezdiffra. In a very short period of time, I think about where we were last year in this meeting, you know, we've really changed profile to being, instead of a company with a promising asset, a company that has a great asset, that has mega blockbuster potential, that now is building its next chapter with a pipeline. Not to even mention the trials that we have ongoing that are gonna read out in both 2027, the F4C trial. Mm-hmm ... and then in 2028, our outcomes trial. How should we think about the main sources of upside or downside to current, full year 2026 Rezdiffra expectation? You mentioned the $1.3 billion run rate. Consensus now starts at about $1.48 billion. That's about 50% up from full year 2025, but that also corresponds to the 50% increase in diagnosed patients that you guys mentioned. As you see this $1.5 billion consensus, do you feel like that's easily achievable with the trends that you're seeing right now, or could you grow share while the market, while the TAM sort of grows at the doctor's office as well? Yeah. Well, look, I think this is all based on coming off a really strong Q4 and momentum that we're carrying- Mm-hmm ... from 2025 into 2026. As we look at the full year, yeah, we're comfortable with consensus where it is. I mean, I wouldn't say anything is ever easy. You said, is it easily achievable? Nothing's easily achievable. You've got to work hard. You've got to be executing-. You make it look so easy. on the plans. You know, thank you for saying that. It isn't easy. I mean, like, we have had to... I think people forget that we've had to build a market from scratch. Mm-hmm. There wasn't a blueprint. There were other markets we could look to to see how they evolved. I mean, we look at, you know, RA, psoriasis, IBD, which are over $20 billion markets with, you know. Mm-hmm ... 10 to 15 products, and they're still growing after, you know, 25, 30 years. There are blueprints like that, but when you actually have to build from scratch, it's really hard work. I think we started with great product, we added great people, we had a great strategy, and we have been executing one thing after another. 2026, we see this continued momentum. We talk about Q1 is we're subject to the Q- All the challenges. Yep. All the Q1 effects. I mean, we've had a lot of questions actually on what is this Q1 effect that you're talking about? Right. What does it mean? You know, patients have to, if they're changing insurance or get verified, et cetera, with insurance, it leads to missed prescriptions. They may miss a prescription or they may miss 2 prescriptions, that means the patient's worth less, so to speak. Mm-hmm ... from a revenue perspective. That sorts itself out through the quarter, and by the time you get to the end of the quarter, they're back on. In Q2, you have more of a full quarter effect. We also have, though, in Q1 of this year, this 0 to contracting effect in commercial lives. Mm-hmm. Right. That's just one other thing that we have to get through. This is the step up in the gross-. The step up in We'll ask about that. Mm-hmm. ... in the gross to net. Look, we're in a really strong position for not only 2026, but as we look towards the future. As you think about the risks to consensus, how is Madrigal mitigating these risks, either taking care of the unexpected ones or getting out ahead, especially as continuing conversation from investors about headwinds from GLP-1s, oral or injected, that you're observing? Well, look, we see way more opportunities than risks. I mean, we're at the very beginning of a market. You know, we talked about, maybe we'll talk about Epi a little bit later, we are less than 12% penetrated into the original 315,000. That is the absolute beginning of a market. We feel good about that. GLP-1s, look, we know GLP-1s are being used, certainly not to the detriment of Rezdiffra. You know, in fact, as we were running into the last earnings call, the prior week had our best NBRx week ever since launch, that's in the presence of Wegovy that was approved, I think, in August, also, oral Wegovy, which, you know, had received a lot of attention. We're not seeing an impact. What we are seeing, though, is having another company out there talking about MASH helping to drive awareness. We think we win in that equation because we've got the best profile product, we believe. Are all intended insurance plans at this point negotiated and sorted, for lack of a better word? I think one of the... Are there any new payer agreements to be renegotiated over the course of the year? There seems to be significant investor concern that gross to net is gonna go up even further. Even though you guys have clearly said, like, high 30s stable, it keeps coming up. Look, gross to net, let's just first of all talk about the commercial contracting. Virtually all of the commercial contracting is in place for, 2026. You have some downstream accounts that, will come in throughout the year. For the most part- What do you mean by downstream accounts? If you have the payer and they have a group of accounts that fall under whatever decision they make, you've got a few accounts that don't have to follow the policy. Oh, they have to decide. They have to decide. Okay they want to accept that or not. The overwhelming majority of the business is locked in. Mm-hmm. There's, you know, there's no news there. That's on the commercial side. You know, we're in a very strong place. Remember, what we contracted for was first line access- Mm-hmm ... no step through Wegovy, and then if we had any utilization management criteria that we wanted to improve... Yeah ... we would put that in the agreement as well. you know, we're in a really great spot. Including prescribers? Pardon me? I mean, that was something we talked about, like, before there was a restriction around who could prescribe, the GIs, et cetera. That's opened up a little bit. no. I mean, that's still, typically it's specialists, so HEPS, GIs. Still ... endocrinology. Yep. Okay. Otherwise it's either them or in consultation with one of them. Mm-hmm. Okay. Yeah, and that's something that we're not trying to remove. We believe that this is a specialty disease that specialists should write the prescription for, and that's how we have organized ourself to call on the 14,000 specialists that we're talking about and that we targeted, with 6,000 being the real super high targets that we focus on. On the left to-do list, that's really not gonna drive the gross to net any further. I just wanted to say one thing, if that's okay. Mm-hmm. Yeah. On the gross to net, you said something about stabilizing at the high thirties. Mm-hmm. That's for 2026. Mm-hmm. Yeah. that's right quarter. Right. I think the next part of your question is, we have to think about Medicare reimbursement as well. Mm-hmm. we did say that you'll see some. We're negotiating now for 2027. Seven, right. You'll see somewhat of a step up, not to the extent what we saw with. Mm-hmm The commercial, the impact of the commercial contracting. You will see a step up in 2027 before it stabilizes. Mm-hmm you know, more broadly. Further. Yeah. On the Q1 call, Marty, you gave commentary that revenue could be down mid to high single digits. Can you give any meaningful color or narrowing of those expectations now that we're more than halfway Well, we're through Q1. How should we think about A, 2Q growth and B, profitability as it comes? I'll take that. Yeah, go ahead. Okay. No, no more narrowing. We thought we did a really good job in looking at the analogs. Mm-hmm. Companies, you know, big brand, in looking at the effect, the Q1 effect, that they're down mid-to-high single-digits, you know, every Q1. For us it's basically the same. We went into great detail about not only do we have the Q1 effect of patients getting reverified, but also the impact of our commercial contracting, yet we're still in with the analogs at the mid-to-high single-digit decline for Q1. We think we're doing very well coming into Q1. What does that mean for Q2? The important piece of the puzzle that Bill talked about on the call was that, at quarter end, we give a net patient add every quarter, thus far, and we anticipate that to steadily add from Q4 to Q1 and beyond as we grow into 2026 and, you know, achieve that, you know, considerable growth for 2026 that we talked about earlier with the consensus number, et cetera. In order to do that, you're gonna have acceleration of net sales from Q1 into Q2, Q3, et cetera. Mm-hmm. Although the patient adds at the end of the quarter, the net patient adds will remain the same, steadily adding through the year. It's just the revenue driven by. Correct. For when it's filled and stuff like that. It's the Q1 effect of when it's filled. Yeah. Correct. profitability. Oh, yes. Profitability. Profitability is inevitable, and it's on the horizon. What we said for 2026 is that we're doing everything we can to support the top-line growth of this business, and we're continuing to invest, particularly in SG&A, to make sure that top line continues to grow. We're not gonna get behind that. At some point, the strength of the growth of the top line is gonna outstrip the rate of growth in a spend. We'll see profitability. Like I said, it's on the horizon. If you look at our past two quarters, even with our, on a cash flow basis, if you strip out the effect of one-time BD charges, we're already in cash flow positive situation last two quarters. We have a lot of strength to our P&L. You know, we'll see that more after 2026. You're not gonna let them bring back the caviar and smoked salmon to the liver meetings like during the Hep C days? We still can't outspend our projected top line growth. Yeah. Are there continued signals from endos, wanting to prescribe Rezdiffra? This was one of the commercial efforts that you guys started. How are your efforts in detailing them progressing? Yeah. We started that, we put our team in place in Q4. It adds about 2,000 additional targets- Mm-hmm ...to our list. You know, they're coming along just as anticipated. First of all, the reason we went there is because we had endocrinologists that were asking us to come because they had MASH patients. Mm-hmm. Which is kind of ironic when you think about it, since they are the biggest users of GLP-1s. If GLP-1s in themselves were sufficient, they wouldn't need Rezdiffra. Right. The reality is they do. We're walking them through kind of the wiring of the system, just like. Well, they're the ones. gastroenterologist and hepatologist had to go through. Yeah. They're the ones who know how to use them the best too. Yeah the GLP-1s. That's correct. their tolerability, so they should have maximum success rate with the GLP-1s. Yeah. One would think. Yeah. Again, gives us additional enthusiasm about the future. Right now, though, it's still pretty early. The awareness is there. Mm-hmm. They have to think through how they're going to utilize NITs, et cetera. Mm-hmm ...just like the Heps and GIs did, and make sure that they have access to an NIT, how they're going to bring somebody through the office, et cetera. That just takes some time, like everyone else. Mm-hmm We're seeing really, positive early signs and continue to see that. We'll see that grow in 26 and beyond. Is that an upside lever to your internal expectations for 2026 and 2027, Lee, endos? it's built into. It's built in. It's built into our... Okay all of our forecasting. What did they tell you about a GLP-1 versus resmetirom? For some patients, I mean, there may be some patients who have never seen a GLP-1 before and end up on their doorstep, and they can't get a GI appointment, et cetera. Like, you know, how does an endo see a first-time patient versus a gastro? Well, they tend to be saying that. They don't talk so much about GLP-1s. Mm-hmm. They tend to be saying, "I need something for MASH because what I have isn't sufficient. Mm-hmm. That's why they wanna understand how to use it. Mechanistically, they're really interested in it and believe that it's something that can help their patients. I think that they've already made the call that either they can't dose titrate up to 2.4, which is the effective dose. Yeah ...or stay there long enough that they want another therapy. Let's briefly address ex-U.S. before moving on to F4. What is your expected contribution, especially Europe, to peak revenue growth? What should we think about in terms of potential for 2027 beyond? Because you've clearly stated that 2026 will still continue to be minimal. How does MFN and ongoing HTA discussions factor into your minimal guidance for 2026 and what you believe for 2027 and beyond? Yeah. Look, 26 is a U.S. year, right? Just to be clear with that. You know, we're at the really tip of the spear when it comes to products launching in an MFN era. You know, Europe is not going to immediately just accept U.S. pricing. Mm-hmm. You know, it's something that they have to think about. It's something that they weren't planning for. It's something that they have to, spend some time, give some thought, and it'll evolve. It won't happen overnight. I think in the long term. Mm-hmm ...year- You mean, like, three plus years? Yeah, I think when you look out in the, you know, three-five year range. Okay everything will settle out, and you'll have, ex US, being a meaningful part of. Mm-hmm ...a launch. Okay. There's still a lot of detail that's gotta get worked out between, now and then. Mm-hmm. We don't have an answer yet because we're just going through these processes now. As we get more information, we'll be able to read out. I mean, we made the decision to launch, full launch in. Mm-hmm ...uh, Germany- Yep ...which started last year. We haven't built out in any other country yet. Right. It'll be dependent upon the HTA discussions. The good news is, as you know, we're starting from a cost-effective place. When you look at ICER's assessment of Rezdiffra in the U.S., we were considered cost-effective. Mm-hmm. Two years later, they did another assessment, and they put us in the high-value category, which meant that it was fairly priced and of significant value to patients and society. That's a great platform to start from when we go to Europe. With Europe, you know, the price that we are offering, the European countries is a blended U.S. government. Mm-hmm ...price, and that's something which is just not what they're used to seeing. Mm-hmm. We're in those discussions. We're hopeful that we will be successful through them. something more along, around the lines of that 23% discount versus the 30%. It's- plus that my models usually reflect. The price is about, $39,500. Okay. Okay. Got it. Let's. Japan. Just a minute on Japan. Yeah. Is Japan different, or is it part of this whole discussion? Japan's on the list as well. Okay. of countries that, we'd like to pursue- Yeah. approval in. Okay. F4. This is probably gonna be the first phase III F4 MASH trial to read out. What magnitude of effect would you consider clinically meaningful for regulators in commercial success? Not just, like, a statistically significant reduction in events, but, like, when does that start to make sense for clinicians? When does it start to make sense for payers? I mean, I think you've sort of answered your own question, right? It will be the first trial to read out in F4C. This is an incredibly high unmet need population. I think the answer is it's really something that achieves statistical significance and is approvable. Anything. Yeah. Can get to patients. Absolutely. What's the powering on that then? The powering- We haven't talked a lot about the details of the powering of the trial. I can give you some of the... Mm-hmm. -sort of parameters that we've talked about. Yeah. In general, when you look at the F4C population, you know, it's a pretty heterogeneous group. You have people who've just recently transitioned from F3 into cirrhosis. Mm-hmm. You've got people who are right on the cusp of decompensation, and they're the ones who have clinically significant portal hypertension. Mm-hmm. Haven't yet had an event, right? Mm-hmm. One of the important things is making sure you have an enriched population for that latter group to make sure you've got enough people in the study who are gonna be on the cusp of having those events. Mm-hmm. You can measure an effect size. Based on that enrichment, we expect a placebo event rate somewhere in the 5%-10% range. There's some publications out there where, you know, there are some high-level assessments of powering and study design, which are in the general range. Mm-hmm. -of, an effect size of 50% to 35%. How sure are you, based on prior data, that these patients aren't too relentlessly on their march towards decompensation that you can't pull them back? I'm so glad you asked that question. This is where the 122 patient open label. Yeah. really tells us some really important information. Okay. so we had a cohort of F4C patients, in one of the earlier studies. Mm-hmm. Yep. exposed to resmetirom now for two years, and we showed these data last year. Again, very similar baseline characteristics as the people enrolled in the MAESTRO outcomes randomized trial. Mm-hmm. A lot of those patients with clinically significant portal hypertension. Right. The CSPC. Yeah. The ones right on the cusp of decompensation. What we see in that population is a shift towards lower portal hypertension risk scores called. Mm-hmm. Baveno classification. Even in the sickest patients and the people already with clinically significant portal hypertension, we can shift those people into lower classifications of clinically significant portal hypertension. You feel that between the Baveno and the portal hypertension, that's the best proxy for events? Yeah. The Baveno criteria and clinically significant portal hypertension are very good predictors of liver-related events. Mm-hmm. Right? If you can hold them back on that, they're savable. Correct. Exactly. Got it. Oh, I lost my space. Well, I'll just add that. Mm-hmm. there are other data. We looked at clinically significant portal hypertension, and that sort of classification shift, but we also saw important changes in other biomarkers like. Mm-hmm. MRE, MR elastography, and liver function tests that also sort of, you know, trended in the right direction. Can you review what the main operational risks are to the timeline for 2027 data? I think that's been... A big fear is that... For the outcome study. For the outcome study. Yeah. Yeah. You're gonna have 2027 data, and they're gonna open up the envelope you're gonna be underpowered. Well, yeah. I mean, look, it's an event-driven trial, right? if you need. When we have enough events, I mean, look, we're not gonna. December 31st isn't gonna come, and if we haven't had enough events, we're gonna say it, the study's over. We're gonna make sure that we have enough events. Mm-hmm. It is tracking towards- You're tracking towards enough events. 27, we're gonna be pragmatic and see what happens. Understood. Is that- Yeah. Is that a fair- Exactly. Okay. I think with respect to, you know, like any outcomes trial, the key is retaining patients in the study, and we've done, I think, a great job at keeping patients in this study. As Bill said, it's really about getting to that target number of events. How do you see positive or negative outcome study from this trial impacting whether it's Rezdiffra's label expansion, potentially destabilizing the accelerator approval or market opportunity revenue trajectory? Yep. Well, look, we've talked about this being a potential doubling of the opportunity. Fewer patients. There's about 235,000 F4C patients. This was when we read it out in 2013. Fewer patients, but higher unmet needs, we would expect- Mm-hmm. increased penetration into that faster. It's a great opportunity for us. I think it also has a carry-through to F2, F3, where people will see, well, if it's working in F4C, another reason to believe in F2, F3. Mm-hmm. I think that, what we have, and, you know, nobody else has this, we already have, you know, over 36,000 patients on drug. By the time we read out and the time we get approval, we're gonna have that much more in our denominator, just that much more experience and certainty about the profile of the brand for when you start to write for F4C. I have left... Oh, go ahead. I was just gonna add that the, you know, a positive F4C study opens the F4C indication itself, plus it gives us full approval on F2, F3. Right. All right. I have left myself 5 minutes to go over your oral GLP-1 ERVO and the siRNA programs. Dave, which one should I start with? I would start with ERVO. Okay, let's start with ERVO. How are you approaching the combo dose selection, and what's the most important measurement when you're evaluating dose selection? Yeah. I mean, just for a bit of background. Yeah. ervogastat's a DGAT2 inhibitor that we recently licensed in from Pfizer. It had actually been through a phase II development program, so we know a lot about this drug already. And including the dose range. Mm-hmm ... which helps us a lot. They've sorted through, they... Pfizer- Yeah ... went through? Okay. They had some- All right. They had dose ranging. Mm-hmm ... data in their phase II program. Mm-hmm. That helps us a lot and some of the measures that they used are the same that we've used with resmetirom, for example, MRI-PDFF, which is reduction of fat content in the liver, and we see ervogastat's a very strong reducer of hepatic fat. Why, why is that important? That's important because there's a strong relationship between resmetirom's reduction of PDFF and improvement in fibrosis. The concept here is because of the two complementary mechanisms of action of these two drugs, we'll be able to get more fat reduction out of the liver, push more patients into that high responder range, and get better anti-fibrotic efficacy- Mm-hmm with the combination. That's essentially the idea behind it. timelines. Uh- ... for the ERVO program right now? Yeah. You know, all the time, you know, when you in-license a program, there's a little bit of block and blocking and tackling, updating regulatory documents, all that kind of stuff. We'll conduct a drug-drug interaction study with resmetirom and ervogastat later this year, go to the FDA, talk about combination drug development studies in phase II. Interesting And do that in 2027. 2027, like a factorial start? something like that, yeah. Something like that. Got it. Yeah. MGL-2086, this is your oral GLP-1. Remind us what scaffold that is and how it differentiates from existing GLP-1s in terms of efficacy, safety, convenience. Yeah. It's on the orforglipron scaffold. Mm-hmm. That's... There are a few things that were attractive about the product. It's on the orforglipron scaffold. The preclinical data were all done by CSPC, our partner in China. Actually, they compared an to orforglipron in a lot of the studies, so we can get a good sense of the relative efficacy of the study, preclinically at least. Mm-hmm. That sort of de-risks it for us. Then from a chemical standpoint, it looks like it should be combinable with resmetirom into a fixed-dose combination. In, like, a co-formulation tablet kind of thing? That would be the idea. Mm-hmm. Yeah, exactly. I think for a lot of reasons, 2086 was a great opportunity. Mm-hmm for us and looks like it could be a great combination product for us. MGL-2086, that's going to go into phase I as a monotherapy. Yes this year? So- Okay. 2027 Yeah ... we'll start talking about combinations. The usual sort of early phase drug development stuff to start with. Your GalNAc conjugated siRNAs in the last minute or so, how are you going to prioritize which targets to advance into clinical development, when could we expect, like, preclinical data? Because, you know, with RNA mechanisms, preclinical, especially non-human primate data, can be particularly meaningful. Yeah, I mean, first of all, it was a great opportunity to work with Ribocure. They're a company based in Gothenburg and also in China. A lot of, you know, really great experience with siRNA technology, and, you know, a great team over there. What we've talked about is we've done a deal on six targets. Mm-hmm. We haven't been specific about the targets yet. All of them are early. They're all preclinical, at this phase, so it's a bit premature for us to talk about exactly what the targets are. As we get more data and we have more to share, we'll of course update on that. Don't expect preclinical data in 2026 or anytime? TBD. TBD. great. With that, we are at time. Thank you, guys. Thanks, Victor. Thank you, Rachel. Thank you for the insight.

Speaker 4: All right, let's get started. Oh, nice full room here. Welcome everyone to the Madrigal Fireside Chat at the 46th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral. With us here from Madrigal, in order, is Bill Sibold, CEO, David Soergel, CMO, and Mardi Dier, CFO. Welcome everyone. Thank you for being here. Maybe let's start with revenue growth, and company goals. We came off another great earnings report. The launch is going exceptionally well, and at the same time you did 3 BD deals in about six months, like within, I don't know, 14 months of Dave joining, to build the pipeline. Before we get into the questions, maybe Bill, can you just give a brief, like three-minute update on the strategy and performance so far this year? All right, let's get started. all right let's get started Oh, nice full room here. oh nice full room here Welcome everyone to the Madrigal Fireside Chat at the 46th Annual TD Cowen Healthcare Conference. welcome everyone to the madrigal fireside chat at the 46th annual td cowen healthcare conference I'm covering analyst Ritu Baral. i'm covering analyst ritu baral With us here from Madrigal, in order, is Bill Sibold, CEO, David Soergel, CMO, and Mardi Dier, CFO. with us here from madrigal in order is bill sibold ceo david soergel cmo and mardi dier cfo Welcome everyone. welcome everyone Thank you for being here. thank you for being here Maybe let's start with revenue growth, and company goals. maybe let's start with revenue growth and company goals We came off another great earnings report. we came off another great earnings report The launch is going exceptionally well, and at the same time you did 3 BD deals in about six months, like within, I don't know, 14 months of Dave joining, to build the pipeline. the launch is going exceptionally well and at the same time you did 3 bd deals in about six months like within i don't know 14 months of dave joining to build the pipeline Before we get into the questions, maybe Bill, can you just give a brief, like three-minute update on the strategy and performance so far this year? before we get into the questions maybe bill can you just give a brief like three-minute update on the strategy and performance so far this year

Speaker 1: Yeah. Ritu, first of all, thanks for having us. It's always a great moment of the year to be here. As you said, things are going just great. Taking a look at Rezdiffra, off to a strong start in its Q7 of launch, annualizing at $1.3 billion. Market growing at about 50% over two years. Because of the current performance and what we anticipate for the future with the market growth and just with continued penetration- Yeah. yeah Ritu, first of all, thanks for having us. ritu first of all thanks for having us It's always a great moment of the year to be here. it's always a great moment of the year to be here As you said, things are going just great. as you said things are going just great Taking a look at Rezdiffra, off to a strong start in its Q7 of launch, annualizing at $1.3 billion. taking a look at rezdiffra off to a strong start in its q7 of launch annualizing at $1.3 billion Market growing at about 50% over two years. market growing at about 50% over two years Because of the current performance and what we anticipate for the future with the market growth and just with continued penetration- because of the current performance and what we anticipate for the future with the market growth and just with continued penetration-

Speaker 4: 50% is diagnosed patients? 50% is diagnosed patients? 50% is diagnosed patients

Speaker 1: 50% diagnosed patients at the treating physicians that we are calling on. 50% diagnosed patients at the treating physicians that we are calling on. 50% diagnosed patients at the treating physicians that we are calling on

Speaker 4: Oh, okay. Oh, okay. oh okay

Speaker 1: Because of those favorable dynamics, we've gone to start building a pipeline. When you look specifically at 2025, hard to imagine really a better year. As I said, we end up annualizing at over $1 billion- Because of those favorable dynamics, we've gone to start building a pipeline. because of those favorable dynamics we've gone to start building a pipeline When you look specifically at 2025, hard to imagine really a better year. when you look specifically at 2025 hard to imagine really a better year As I said, we end up annualizing at over $1 billion- as i said we end up annualizing at over $1 billion-

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: Close to $1 billion in sales for 2025. Over 36,250 patients on therapy. As we finish the year, we exit, as we talk about this 50% growth in the market. Close to $1 billion in sales for 2025. close to $1 billion in sales for 2025 Over 36,250 patients on therapy. over 36,250 patients on therapy As we finish the year, we exit, as we talk about this 50% growth in the market. as we finish the year we exit as we talk about this 50% growth in the market

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: We've started to build a pipeline I'll get to in a minute. We've started to build a pipeline I'll get to in a minute. we've started to build a pipeline i'll get to in a minute

Speaker 4: Yep Yep yep

Speaker 1: We've also secured 2045 IP for Rezdiffra. We've really put ourselves in a position for long-term growth. The way we thought about the pipeline really is Rezdiffra is a great product. It's a foundational product. It's become quickly the standard of care. How do you make a better product even? We've also secured 2045 IP for Rezdiffra. we've also secured 2045 ip for rezdiffra We've really put ourselves in a position for long-term growth. we've really put ourselves in a position for long-term growth The way we thought about the pipeline really is Rezdiffra is a great product. the way we thought about the pipeline really is rezdiffra is a great product It's a foundational product. it's a foundational product It's become quickly the standard of care. it's become quickly the standard of care How do you make a better product even? how do you make a better product even

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: How do we get a better response in the overall population, or how do we identify a subgroup of patients that may respond better? It's such a foundational therapy when you look across all subgroups, subpopulations, the effect is pretty much the same. As we add new mechanisms of action, as you said, in the last six months, we've gone from a company that has a single product in the pipeline to a company that now has over 10 products in the pipeline. How do we get a better response in the overall population, or how do we identify a subgroup of patients that may respond better? how do we get a better response in the overall population or how do we identify a subgroup of patients that may respond better It's such a foundational therapy when you look across all subgroups, subpopulations, the effect is pretty much the same. it's such a foundational therapy when you look across all subgroups subpopulations the effect is pretty much the same As we add new mechanisms of action, as you said, in the last six months, we've gone from a company that has a single product in the pipeline to a company that now has over 10 products in the pipeline. as we add new mechanisms of action as you said in the last six months we've gone from a company that has a single product in the pipeline to a company that now has over 10 products in the pipeline

Speaker 4: Yeah. Yeah. yeah

Speaker 1: The idea is we will look at combination therapy with Rezdiffra to see if we can get a better response for the whole population or a subgroup and take that forward fast, otherwise kill it fast. The idea is we will look at combination therapy with Rezdiffra to see if we can get a better response for the whole population or a subgroup and take that forward fast, otherwise kill it fast. the idea is we will look at combination therapy with rezdiffra to see if we can get a better response for the whole population or a subgroup and take that forward fast otherwise kill it fast

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: We started with an oral GLP-1. We think that mechanistically makes a lot of sense because we know from our trials that just with over 5% weight loss, we can get a better effect with Rezdiffra. We did the DGAT2 with Pfizer. We think mechanistically makes a lot of sense. Maybe we'll talk about that a little bit later. We started with an oral GLP-1. we started with an oral glp-1 We think that mechanistically makes a lot of sense because we know from our trials that just with over 5% weight loss, we can get a better effect with Rezdiffra. we think that mechanistically makes a lot of sense because we know from our trials that just with over 5% weight loss we can get a better effect with rezdiffra We did the DGAT2 with Pfizer. we did the dgat2 with pfizer We think mechanistically makes a lot of sense. we think mechanistically makes a lot of sense Maybe we'll talk about that a little bit later. maybe we'll talk about that a little bit later

Speaker 4: Yep. Yep. yep

Speaker 1: siRNA, we did six programs that we have brought in that we are directing towards MASH as well. We like it. It's liver-directed therapy as well, and think that there's good rationale for combination with Rezdiffra. In a very short period of time, I think about where we were last year in this meeting, you know, we've really changed profile to being, instead of a company with a promising asset, a company that has a great asset, that has mega blockbuster potential, that now is building its next chapter with a pipeline. Not to even mention the trials that we have ongoing that are gonna read out in both 2027, the F4C trial. siRNA, we did six programs that we have brought in that we are directing towards MASH as well. sirna we did six programs that we have brought in that we are directing towards mash as well We like it. we like it It's liver-directed therapy as well, and think that there's good rationale for combination with Rezdiffra. it's liver-directed therapy as well and think that there's good rationale for combination with rezdiffra In a very short period of time, I think about where we were last year in this meeting, you know, we've really changed profile to being, instead of a company with a promising asset, a company that has a great asset, that has mega blockbuster potential, that now is building its next chapter with a pipeline. in a very short period of time i think about where we were last year in this meeting you know we've really changed profile to being instead of a company with a promising asset a company that has a great asset that has mega blockbuster potential that now is building its next chapter with a pipeline Not to even mention the trials that we have ongoing that are gonna read out in both 2027, the F4C trial. not to even mention the trials that we have ongoing that are gonna read out in both 2027 the f4c trial

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... and then in 2028, our outcomes trial. ... and then in 2028, our outcomes trial. and then in 2028 our outcomes trial

Speaker 4: How should we think about the main sources of upside or downside to current, full year 2026 Rezdiffra expectation? You mentioned the $1.3 billion run rate. Consensus now starts at about $1.48 billion. That's about 50% up from full year 2025, but that also corresponds to the 50% increase in diagnosed patients that you guys mentioned. As you see this $1.5 billion consensus, do you feel like that's easily achievable with the trends that you're seeing right now, or could you grow share while the market, while the TAM sort of grows at the doctor's office as well? How should we think about the main sources of upside or downside to current, full year 2026 Rezdiffra expectation? how should we think about the main sources of upside or downside to current full year 2026 rezdiffra expectation You mentioned the $1.3 billion run rate. you mentioned the $1.3 billion run rate Consensus now starts at about $1.48 billion. consensus now starts at about $1.48 billion That's about 50% up from full year 2025, but that also corresponds to the 50% increase in diagnosed patients that you guys mentioned. that's about 50% up from full year 2025 but that also corresponds to the 50% increase in diagnosed patients that you guys mentioned As you see this $1.5 billion consensus, do you feel like that's easily achievable with the trends that you're seeing right now, or could you grow share while the market, while the TAM sort of grows at the doctor's office as well? as you see this $1.5 billion consensus do you feel like that's easily achievable with the trends that you're seeing right now or could you grow share while the market while the tam sort of grows at the doctor's office as well

Speaker 1: Yeah. Well, look, I think this is all based on coming off a really strong Q4 and momentum that we're carrying- Yeah. yeah Well, look, I think this is all based on coming off a really strong Q4 and momentum that we're carrying- well look i think this is all based on coming off a really strong q4 and momentum that we're carrying-

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... from 2025 into 2026. As we look at the full year, yeah, we're comfortable with consensus where it is. I mean, I wouldn't say anything is ever easy. You said, is it easily achievable? Nothing's easily achievable. You've got to work hard. You've got to be executing-. ... from 2025 into 2026. from 2025 into 2026 As we look at the full year, yeah, we're comfortable with consensus where it is. as we look at the full year yeah we're comfortable with consensus where it is I mean, I wouldn't say anything is ever easy. i mean i wouldn't say anything is ever easy You said, is it easily achievable? you said is it easily achievable Nothing's easily achievable. nothing's easily achievable You've got to work hard. you've got to work hard You've got to be executing-. you've got to be executing-

Speaker 4: You make it look so easy. You make it look so easy. you make it look so easy

Speaker 1: on the plans. You know, thank you for saying that. It isn't easy. I mean, like, we have had to... I think people forget that we've had to build a market from scratch. on the plans. on the plans You know, thank you for saying that. you know thank you for saying that It isn't easy. it isn't easy I mean, like, we have had to... i mean like we have had to I think people forget that we've had to build a market from scratch. i think people forget that we've had to build a market from scratch

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: There wasn't a blueprint. There were other markets we could look to to see how they evolved. I mean, we look at, you know, RA, psoriasis, IBD, which are over $20 billion markets with, you know. There wasn't a blueprint. there wasn't a blueprint There were other markets we could look to to see how they evolved. there were other markets we could look to to see how they evolved I mean, we look at, you know, RA, psoriasis, IBD, which are over $20 billion markets with, you know. i mean we look at you know ra psoriasis ibd which are over $20 billion markets with you know

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... 10 to 15 products, and they're still growing after, you know, 25, 30 years. There are blueprints like that, but when you actually have to build from scratch, it's really hard work. I think we started with great product, we added great people, we had a great strategy, and we have been executing one thing after another. 2026, we see this continued momentum. We talk about Q1 is we're subject to the Q- ... 10 to 15 products, and they're still growing after, you know, 25, 30 years. 10 to 15 products and they're still growing after you know 25 30 years There are blueprints like that, but when you actually have to build from scratch, it's really hard work. there are blueprints like that but when you actually have to build from scratch it's really hard work I think we started with great product, we added great people, we had a great strategy, and we have been executing one thing after another. 2026, we see this continued momentum. i think we started with great product we added great people we had a great strategy and we have been executing one thing after another 2026 we see this continued momentum We talk about Q1 is we're subject to the Q- we talk about q1 is we're subject to the q-

Speaker 4: All the challenges. Yep. All the challenges. all the challenges Yep. yep

Speaker 1: All the Q1 effects. I mean, we've had a lot of questions actually on what is this Q1 effect that you're talking about? All the Q1 effects. all the q1 effects I mean, we've had a lot of questions actually on what is this Q1 effect that you're talking about? i mean we've had a lot of questions actually on what is this q1 effect that you're talking about

Speaker 4: Right. Right. right

Speaker 1: What does it mean? You know, patients have to, if they're changing insurance or get verified, et cetera, with insurance, it leads to missed prescriptions. They may miss a prescription or they may miss 2 prescriptions, that means the patient's worth less, so to speak. What does it mean? what does it mean You know, patients have to, if they're changing insurance or get verified, et cetera, with insurance, it leads to missed prescriptions. you know patients have to if they're changing insurance or get verified et cetera with insurance it leads to missed prescriptions They may miss a prescription or they may miss 2 prescriptions, that means the patient's worth less, so to speak. they may miss a prescription or they may miss 2 prescriptions that means the patient's worth less so to speak

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... from a revenue perspective. That sorts itself out through the quarter, and by the time you get to the end of the quarter, they're back on. In Q2, you have more of a full quarter effect. We also have, though, in Q1 of this year, this 0 to contracting effect in commercial lives. ... from a revenue perspective. from a revenue perspective That sorts itself out through the quarter, and by the time you get to the end of the quarter, they're back on. that sorts itself out through the quarter and by the time you get to the end of the quarter they're back on In Q2, you have more of a full quarter effect. in q2 you have more of a full quarter effect We also have, though, in Q1 of this year, this 0 to contracting effect in commercial lives. we also have though in q1 of this year this 0 to contracting effect in commercial lives

Speaker 4: Mm-hmm. Right. Mm-hmm. mm-hmm Right. right

Speaker 1: That's just one other thing that we have to get through. That's just one other thing that we have to get through. that's just one other thing that we have to get through

Speaker 4: This is the step up in the gross-. This is the step up in the gross-. this is the step up in the gross-

Speaker 1: The step up in The step up in the step up in

Speaker 4: We'll ask about that. Mm-hmm. We'll ask about that. we'll ask about that mm-hmm Mm-hmm. we'll ask about that mm-hmm

Speaker 1: ... in the gross to net. Look, we're in a really strong position for not only 2026, but as we look towards the future. ... in the gross to net. in the gross to net Look, we're in a really strong position for not only 2026, but as we look towards the future. look we're in a really strong position for not only 2026 but as we look towards the future

Speaker 4: As you think about the risks to consensus, how is Madrigal mitigating these risks, either taking care of the unexpected ones or getting out ahead, especially as continuing conversation from investors about headwinds from GLP-1s, oral or injected, that you're observing? As you think about the risks to consensus, how is Madrigal mitigating these risks, either taking care of the unexpected ones or getting out ahead, especially as continuing conversation from investors about headwinds from GLP-1s, oral or injected, that you're observing? as you think about the risks to consensus how is madrigal mitigating these risks either taking care of the unexpected ones or getting out ahead especially as continuing conversation from investors about headwinds from glp-1s oral or injected that you're observing

Speaker 1: Well, look, we see way more opportunities than risks. I mean, we're at the very beginning of a market. You know, we talked about, maybe we'll talk about Epi a little bit later, we are less than 12% penetrated into the original 315,000. That is the absolute beginning of a market. We feel good about that. GLP-1s, look, we know GLP-1s are being used, certainly not to the detriment of Rezdiffra. You know, in fact, as we were running into the last earnings call, the prior week had our best NBRx week ever since launch, that's in the presence of Wegovy that was approved, I think, in August, also, oral Wegovy, which, you know, had received a lot of attention. We're not seeing an impact. Well, look, we see way more opportunities than risks. well look we see way more opportunities than risks I mean, we're at the very beginning of a market. i mean we're at the very beginning of a market You know, we talked about, maybe we'll talk about Epi a little bit later, we are less than 12% penetrated into the original 315,000. you know we talked about maybe we'll talk about epi a little bit later we are less than 12% penetrated into the original 315,000 That is the absolute beginning of a market. that is the absolute beginning of a market We feel good about that. we feel good about that GLP-1s, look, we know GLP-1s are being used, certainly not to the detriment of Rezdiffra. glp-1s look we know glp-1s are being used certainly not to the detriment of rezdiffra You know, in fact, as we were running into the last earnings call, the prior week had our best NBRx week ever since launch, that's in the presence of Wegovy that was approved, I think, in August, also, oral Wegovy, which, you know, had received a lot of attention. you know in fact as we were running into the last earnings call the prior week had our best nbrx week ever since launch that's in the presence of wegovy that was approved i think in august also oral wegovy which you know had received a lot of attention We're not seeing an impact. we're not seeing an impact What we are seeing, though, is having another company out there talking about MASH helping to drive awareness. We think we win in that equation because we've got the best profile product, we believe. What we are seeing, though, is having another company out there talking about MASH helping to drive awareness. what we are seeing though is having another company out there talking about mash helping to drive awareness We think we win in that equation because we've got the best profile product, we believe. we think we win in that equation because we've got the best profile product we believe

Speaker 4: Are all intended insurance plans at this point negotiated and sorted, for lack of a better word? I think one of the... Are there any new payer agreements to be renegotiated over the course of the year? There seems to be significant investor concern that gross to net is gonna go up even further. Even though you guys have clearly said, like, high 30s stable, it keeps coming up. Are all intended insurance plans at this point negotiated and sorted, for lack of a better word? are all intended insurance plans at this point negotiated and sorted for lack of a better word I think one of the... i think one of the Are there any new payer agreements to be renegotiated over the course of the year? are there any new payer agreements to be renegotiated over the course of the year There seems to be significant investor concern that gross to net is gonna go up even further. there seems to be significant investor concern that gross to net is gonna go up even further Even though you guys have clearly said, like, high 30s stable, it keeps coming up. even though you guys have clearly said like high 30s stable it keeps coming up

Speaker 1: Look, gross to net, let's just first of all talk about the commercial contracting. Virtually all of the commercial contracting is in place for, 2026. You have some downstream accounts that, will come in throughout the year. For the most part- Look, gross to net, let's just first of all talk about the commercial contracting. look gross to net let's just first of all talk about the commercial contracting Virtually all of the commercial contracting is in place for, 2026. virtually all of the commercial contracting is in place for 2026 You have some downstream accounts that, will come in throughout the year. you have some downstream accounts that will come in throughout the year For the most part- for the most part-

Speaker 4: What do you mean by downstream accounts? What do you mean by downstream accounts? what do you mean by downstream accounts

Speaker 1: If you have the payer and they have a group of accounts that fall under whatever decision they make, you've got a few accounts that don't have to follow the policy. If you have the payer and they have a group of accounts that fall under whatever decision they make, you've got a few accounts that don't have to follow the policy. if you have the payer and they have a group of accounts that fall under whatever decision they make you've got a few accounts that don't have to follow the policy

Speaker 4: Oh, they have to decide. Oh, they have to decide. oh they have to decide

Speaker 1: They have to decide. They have to decide. they have to decide

Speaker 4: Okay Okay okay

Speaker 1: they want to accept that or not. The overwhelming majority of the business is locked in. they want to accept that or not. they want to accept that or not The overwhelming majority of the business is locked in. the overwhelming majority of the business is locked in

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: There's, you know, there's no news there. That's on the commercial side. You know, we're in a very strong place. Remember, what we contracted for was first line access- There's, you know, there's no news there. there's you know there's no news there That's on the commercial side. that's on the commercial side You know, we're in a very strong place. you know we're in a very strong place Remember, what we contracted for was first line access- remember what we contracted for was first line access-

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ... no step through Wegovy, and then if we had any utilization management criteria that we wanted to improve... ... no step through Wegovy, and then if we had any utilization management criteria that we wanted to improve... no step through wegovy and then if we had any utilization management criteria that we wanted to improve

Speaker 4: Yeah Yeah yeah

Speaker 1: ... we would put that in the agreement as well. you know, we're in a really great spot. ... we would put that in the agreement as well. you know, we're in a really great spot. we would put that in the agreement as well you know we're in a really great spot

Speaker 4: Including prescribers? Including prescribers? including prescribers

Speaker 1: Pardon me? Pardon me? pardon me

Speaker 4: I mean, that was something we talked about, like, before there was a restriction around who could prescribe, the GIs, et cetera. That's opened up a little bit. I mean, that was something we talked about, like, before there was a restriction around who could prescribe, the GIs, et cetera. i mean that was something we talked about like before there was a restriction around who could prescribe the gis et cetera That's opened up a little bit. that's opened up a little bit

Speaker 1: no. I mean, that's still, typically it's specialists, so HEPS, GIs. no. no I mean, that's still, typically it's specialists, so HEPS, GIs. i mean that's still typically it's specialists so heps gis

Speaker 4: Still Still still

Speaker 1: ... endocrinology. Yep. ... endocrinology. endocrinology Yep. yep

Speaker 4: Okay. Okay. okay

Speaker 1: Otherwise it's either them or in consultation with one of them. Otherwise it's either them or in consultation with one of them. otherwise it's either them or in consultation with one of them

Speaker 4: Mm-hmm. Okay. Mm-hmm. mm-hmm Okay. okay

Speaker 1: Yeah, and that's something that we're not trying to remove. We believe that this is a specialty disease that specialists should write the prescription for, and that's how we have organized ourself to call on the 14,000 specialists that we're talking about and that we targeted, with 6,000 being the real super high targets that we focus on. Yeah, and that's something that we're not trying to remove. yeah and that's something that we're not trying to remove We believe that this is a specialty disease that specialists should write the prescription for, and that's how we have organized ourself to call on the 14,000 specialists that we're talking about and that we targeted, with 6,000 being the real super high targets that we focus on. we believe that this is a specialty disease that specialists should write the prescription for and that's how we have organized ourself to call on the 14,000 specialists that we're talking about and that we targeted with 6,000 being the real super high targets that we focus on

Speaker 4: On the left to-do list, that's really not gonna drive the gross to net any further. On the left to-do list, that's really not gonna drive the gross to net any further. on the left to-do list that's really not gonna drive the gross to net any further

Speaker 3: I just wanted to say one thing, if that's okay. I just wanted to say one thing, if that's okay. i just wanted to say one thing if that's okay

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: Yeah. Yeah. yeah

Speaker 3: On the gross to net, you said something about stabilizing at the high thirties. On the gross to net, you said something about stabilizing at the high thirties. on the gross to net you said something about stabilizing at the high thirties

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 3: That's for 2026. That's for 2026. that's for 2026

Speaker 4: Mm-hmm. Yeah. Mm-hmm. mm-hmm Yeah. yeah

Speaker 3: that's right quarter. that's right quarter. that's right quarter

Speaker 4: Right. Right. right

Speaker 3: I think the next part of your question is, we have to think about Medicare reimbursement as well. I think the next part of your question is, we have to think about Medicare reimbursement as well. i think the next part of your question is we have to think about medicare reimbursement as well

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 3: we did say that you'll see some. We're negotiating now for 2027. we did say that you'll see some. we did say that you'll see some We're negotiating now for 2027. we're negotiating now for 2027

Speaker 4: Seven, right. Seven, right. seven right

Speaker 3: You'll see somewhat of a step up, not to the extent what we saw with. You'll see somewhat of a step up, not to the extent what we saw with. you'll see somewhat of a step up not to the extent what we saw with

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 3: The commercial, the impact of the commercial contracting. You will see a step up in 2027 before it stabilizes. The commercial, the impact of the commercial contracting. the commercial the impact of the commercial contracting You will see a step up in 2027 before it stabilizes. you will see a step up in 2027 before it stabilizes

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 3: you know, more broadly. you know, more broadly. you know more broadly

Speaker 4: Further. Further. further

Speaker 3: Yeah. Yeah. yeah

Speaker 4: On the Q1 call, Marty, you gave commentary that revenue could be down mid to high single digits. Can you give any meaningful color or narrowing of those expectations now that we're more than halfway Well, we're through Q1. How should we think about A, 2Q growth and B, profitability as it comes? On the Q1 call, Marty, you gave commentary that revenue could be down mid to high single digits. on the q1 call marty you gave commentary that revenue could be down mid to high single digits Can you give any meaningful color or narrowing of those expectations now that we're more than halfway Well, we're through Q1. can you give any meaningful color or narrowing of those expectations now that we're more than halfway well we're through q1 How should we think about A, 2Q growth and B, profitability as it comes? how should we think about a 2q growth and b profitability as it comes

Speaker 3: I'll take that. I'll take that. i'll take that

Speaker 1: Yeah, go ahead. Yeah, go ahead. yeah go ahead

Speaker 3: Okay. No, no more narrowing. We thought we did a really good job in looking at the analogs. Okay. okay No, no more narrowing. no no more narrowing We thought we did a really good job in looking at the analogs. we thought we did a really good job in looking at the analogs

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 3: Companies, you know, big brand, in looking at the effect, the Q1 effect, that they're down mid-to-high single-digits, you know, every Q1. For us it's basically the same. We went into great detail about not only do we have the Q1 effect of patients getting reverified, but also the impact of our commercial contracting, yet we're still in with the analogs at the mid-to-high single-digit decline for Q1. We think we're doing very well coming into Q1. What does that mean for Q2? Companies, you know, big brand, in looking at the effect, the Q1 effect, that they're down mid-to-high single-digits, you know, every Q1. companies you know big brand in looking at the effect the q1 effect that they're down mid-to-high single-digits you know every q1 For us it's basically the same. for us it's basically the same We went into great detail about not only do we have the Q1 effect of patients getting reverified, but also the impact of our commercial contracting, yet we're still in with the analogs at the mid-to-high single-digit decline for Q1. we went into great detail about not only do we have the q1 effect of patients getting reverified but also the impact of our commercial contracting yet we're still in with the analogs at the mid-to-high single-digit decline for q1 We think we're doing very well coming into Q1. we think we're doing very well coming into q1 What does that mean for Q2? what does that mean for q2 The important piece of the puzzle that Bill talked about on the call was that, at quarter end, we give a net patient add every quarter, thus far, and we anticipate that to steadily add from Q4 to Q1 and beyond as we grow into 2026 and, you know, achieve that, you know, considerable growth for 2026 that we talked about earlier with the consensus number, et cetera. In order to do that, you're gonna have acceleration of net sales from Q1 into Q2, Q3, et cetera. The important piece of the puzzle that Bill talked about on the call was that, at quarter end, we give a net patient add every quarter, thus far, and we anticipate that to steadily add from Q4 to Q1 and beyond as we grow into 2026 and, you know, achieve that, you know, considerable growth for 2026 that we talked about earlier with the consensus number, et cetera. the important piece of the puzzle that bill talked about on the call was that at quarter end we give a net patient add every quarter thus far and we anticipate that to steadily add from q4 to q1 and beyond as we grow into 2026 and you know achieve that you know considerable growth for 2026 that we talked about earlier with the consensus number et cetera In order to do that, you're gonna have acceleration of net sales from Q1 into Q2, Q3, et cetera. in order to do that you're gonna have acceleration of net sales from q1 into q2 q3 et cetera

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 3: Although the patient adds at the end of the quarter, the net patient adds will remain the same, steadily adding through the year. Although the patient adds at the end of the quarter, the net patient adds will remain the same, steadily adding through the year. although the patient adds at the end of the quarter the net patient adds will remain the same steadily adding through the year

Speaker 4: It's just the revenue driven by. It's just the revenue driven by. it's just the revenue driven by

Speaker 3: Correct. Correct. correct

Speaker 4: For when it's filled and stuff like that. For when it's filled and stuff like that. for when it's filled and stuff like that

Speaker 3: It's the Q1 effect of when it's filled. It's the Q1 effect of when it's filled. it's the q1 effect of when it's filled

Speaker 4: Yeah. Yeah. yeah

Speaker 3: Correct. Correct. correct

Speaker 4: profitability. profitability. profitability

Speaker 3: Oh, yes. Profitability. Profitability is inevitable, and it's on the horizon. What we said for 2026 is that we're doing everything we can to support the top-line growth of this business, and we're continuing to invest, particularly in SG&A, to make sure that top line continues to grow. We're not gonna get behind that. At some point, the strength of the growth of the top line is gonna outstrip the rate of growth in a spend. We'll see profitability. Like I said, it's on the horizon. If you look at our past two quarters, even with our, on a cash flow basis, if you strip out the effect of one-time BD charges, we're already in cash flow positive situation last two quarters. We have a lot of strength to our P&L. Oh, yes. oh yes Profitability. profitability Profitability is inevitable, and it's on the horizon. profitability is inevitable and it's on the horizon What we said for 2026 is that we're doing everything we can to support the top-line growth of this business, and we're continuing to invest, particularly in SG&A, to make sure that top line continues to grow. what we said for 2026 is that we're doing everything we can to support the top-line growth of this business and we're continuing to invest particularly in sg&a to make sure that top line continues to grow We're not gonna get behind that. we're not gonna get behind that At some point, the strength of the growth of the top line is gonna outstrip the rate of growth in a spend. at some point the strength of the growth of the top line is gonna outstrip the rate of growth in a spend We'll see profitability. we'll see profitability Like I said, it's on the horizon. like i said it's on the horizon If you look at our past two quarters, even with our, on a cash flow basis, if you strip out the effect of one-time BD charges, we're already in cash flow positive situation last two quarters. if you look at our past two quarters even with our on a cash flow basis if you strip out the effect of one-time bd charges we're already in cash flow positive situation last two quarters We have a lot of strength to our P&L. we have a lot of strength to our p&l You know, we'll see that more after 2026. You know, we'll see that more after 2026. you know we'll see that more after 2026

Speaker 4: You're not gonna let them bring back the caviar and smoked salmon to the liver meetings like during the Hep C days? You're not gonna let them bring back the caviar and smoked salmon to the liver meetings like during the Hep C days? you're not gonna let them bring back the caviar and smoked salmon to the liver meetings like during the hep c days

Speaker 3: We still can't outspend our projected top line growth. Yeah. We still can't outspend our projected top line growth. we still can't outspend our projected top line growth Yeah. yeah

Speaker 4: Are there continued signals from endos, wanting to prescribe Rezdiffra? This was one of the commercial efforts that you guys started. How are your efforts in detailing them progressing? Are there continued signals from endos, wanting to prescribe Rezdiffra? are there continued signals from endos wanting to prescribe rezdiffra This was one of the commercial efforts that you guys started. this was one of the commercial efforts that you guys started How are your efforts in detailing them progressing? how are your efforts in detailing them progressing

Speaker 1: Yeah. We started that, we put our team in place in Q4. It adds about 2,000 additional targets- Yeah. yeah We started that, we put our team in place in Q4. we started that we put our team in place in q4 It adds about 2,000 additional targets- it adds about 2,000 additional targets-

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...to our list. You know, they're coming along just as anticipated. First of all, the reason we went there is because we had endocrinologists that were asking us to come because they had MASH patients. ...to our list. ...to our list You know, they're coming along just as anticipated. you know they're coming along just as anticipated First of all, the reason we went there is because we had endocrinologists that were asking us to come because they had MASH patients. first of all the reason we went there is because we had endocrinologists that were asking us to come because they had mash patients

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: Which is kind of ironic when you think about it, since they are the biggest users of GLP-1s. If GLP-1s in themselves were sufficient, they wouldn't need Rezdiffra. Which is kind of ironic when you think about it, since they are the biggest users of GLP-1s. which is kind of ironic when you think about it since they are the biggest users of glp-1s If GLP-1s in themselves were sufficient, they wouldn't need Rezdiffra. if glp-1s in themselves were sufficient they wouldn't need rezdiffra

Speaker 4: Right. Right. right

Speaker 1: The reality is they do. We're walking them through kind of the wiring of the system, just like. The reality is they do. the reality is they do We're walking them through kind of the wiring of the system, just like. we're walking them through kind of the wiring of the system just like

Speaker 4: Well, they're the ones. Well, they're the ones. well they're the ones

Speaker 1: gastroenterologist and hepatologist had to go through. gastroenterologist and hepatologist had to go through. gastroenterologist and hepatologist had to go through

Speaker 4: Yeah. They're the ones who know how to use them the best too. Yeah. yeah They're the ones who know how to use them the best too. they're the ones who know how to use them the best too

Speaker 1: Yeah Yeah yeah

Speaker 4: the GLP-1s. the GLP-1s. the glp-1s

Speaker 1: That's correct. That's correct. that's correct

Speaker 4: their tolerability, so they should have maximum success rate with the GLP-1s. their tolerability, so they should have maximum success rate with the GLP-1s. their tolerability so they should have maximum success rate with the glp-1s

Speaker 1: Yeah. One would think. Yeah. yeah One would think. one would think

Speaker 4: Yeah. Yeah. yeah

Speaker 1: Again, gives us additional enthusiasm about the future. Right now, though, it's still pretty early. The awareness is there. Again, gives us additional enthusiasm about the future. again gives us additional enthusiasm about the future Right now, though, it's still pretty early. right now though it's still pretty early The awareness is there. the awareness is there

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: They have to think through how they're going to utilize NITs, et cetera. They have to think through how they're going to utilize NITs, et cetera. they have to think through how they're going to utilize nits et cetera

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...just like the Heps and GIs did, and make sure that they have access to an NIT, how they're going to bring somebody through the office, et cetera. That just takes some time, like everyone else. ...just like the Heps and GIs did, and make sure that they have access to an NIT, how they're going to bring somebody through the office, et cetera. ...just like the heps and gis did and make sure that they have access to an nit how they're going to bring somebody through the office et cetera That just takes some time, like everyone else. that just takes some time like everyone else

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: We're seeing really, positive early signs and continue to see that. We'll see that grow in 26 and beyond. We're seeing really, positive early signs and continue to see that. we're seeing really positive early signs and continue to see that We'll see that grow in 26 and beyond. we'll see that grow in 26 and beyond

Speaker 4: Is that an upside lever to your internal expectations for 2026 and 2027, Lee, endos? Is that an upside lever to your internal expectations for 2026 and 2027, Lee, endos? is that an upside lever to your internal expectations for 2026 and 2027 lee endos

Speaker 1: it's built into. it's built into. it's built into

Speaker 4: It's built in. It's built in. it's built in

Speaker 1: It's built into our... It's built into our... it's built into our

Speaker 4: Okay Okay okay

Speaker 1: all of our forecasting. all of our forecasting. all of our forecasting

Speaker 4: What did they tell you about a GLP-1 versus resmetirom? For some patients, I mean, there may be some patients who have never seen a GLP-1 before and end up on their doorstep, and they can't get a GI appointment, et cetera. Like, you know, how does an endo see a first-time patient versus a gastro? What did they tell you about a GLP-1 versus resmetirom? what did they tell you about a glp-1 versus resmetirom For some patients, I mean, there may be some patients who have never seen a GLP-1 before and end up on their doorstep, and they can't get a GI appointment, et cetera. for some patients i mean there may be some patients who have never seen a glp-1 before and end up on their doorstep and they can't get a gi appointment et cetera Like, you know, how does an endo see a first-time patient versus a gastro? like you know how does an endo see a first-time patient versus a gastro

Speaker 1: Well, they tend to be saying that. They don't talk so much about GLP-1s. Well, they tend to be saying that. well they tend to be saying that They don't talk so much about GLP-1s. they don't talk so much about glp-1s

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: They tend to be saying, "I need something for MASH because what I have isn't sufficient. They tend to be saying, "I need something for MASH because what I have isn't sufficient. they tend to be saying "i need something for mash because what i have isn't sufficient

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: That's why they wanna understand how to use it. Mechanistically, they're really interested in it and believe that it's something that can help their patients. I think that they've already made the call that either they can't dose titrate up to 2.4, which is the effective dose. That's why they wanna understand how to use it. that's why they wanna understand how to use it Mechanistically, they're really interested in it and believe that it's something that can help their patients. mechanistically they're really interested in it and believe that it's something that can help their patients I think that they've already made the call that either they can't dose titrate up to 2.4, which is the effective dose. i think that they've already made the call that either they can't dose titrate up to 2.4 which is the effective dose

Speaker 4: Yeah Yeah yeah

Speaker 1: ...or stay there long enough that they want another therapy. ...or stay there long enough that they want another therapy. ...or stay there long enough that they want another therapy

Speaker 4: Let's briefly address ex-U.S. before moving on to F4. What is your expected contribution, especially Europe, to peak revenue growth? What should we think about in terms of potential for 2027 beyond? Because you've clearly stated that 2026 will still continue to be minimal. How does MFN and ongoing HTA discussions factor into your minimal guidance for 2026 and what you believe for 2027 and beyond? Let's briefly address ex-U.S. before moving on to F4. let's briefly address ex-u.s before moving on to f4 What is your expected contribution, especially Europe, to peak revenue growth? what is your expected contribution especially europe to peak revenue growth What should we think about in terms of potential for 2027 beyond? what should we think about in terms of potential for 2027 beyond Because you've clearly stated that 2026 will still continue to be minimal. because you've clearly stated that 2026 will still continue to be minimal How does MFN and ongoing HTA discussions factor into your minimal guidance for 2026 and what you believe for 2027 and beyond? how does mfn and ongoing hta discussions factor into your minimal guidance for 2026 and what you believe for 2027 and beyond

Speaker 1: Yeah. Look, 26 is a U.S. year, right? Just to be clear with that. You know, we're at the really tip of the spear when it comes to products launching in an MFN era. You know, Europe is not going to immediately just accept U.S. pricing. Yeah. yeah Look, 26 is a U.S. year, right? look 26 is a u.s year right Just to be clear with that. just to be clear with that You know, we're at the really tip of the spear when it comes to products launching in an MFN era. you know we're at the really tip of the spear when it comes to products launching in an mfn era You know, Europe is not going to immediately just accept U.S. pricing. you know europe is not going to immediately just accept u.s pricing

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: You know, it's something that they have to think about. It's something that they weren't planning for. It's something that they have to, spend some time, give some thought, and it'll evolve. It won't happen overnight. I think in the long term. You know, it's something that they have to think about. you know it's something that they have to think about It's something that they weren't planning for. it's something that they weren't planning for It's something that they have to, spend some time, give some thought, and it'll evolve. it's something that they have to spend some time give some thought and it'll evolve It won't happen overnight. it won't happen overnight I think in the long term. i think in the long term

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...year- ...year- ...year-

Speaker 4: You mean, like, three plus years? You mean, like, three plus years? you mean like three plus years

Speaker 1: Yeah, I think when you look out in the, you know, three-five year range. Yeah, I think when you look out in the, you know, three-five year range. yeah i think when you look out in the you know three-five year range

Speaker 4: Okay Okay okay

Speaker 1: everything will settle out, and you'll have, ex US, being a meaningful part of. everything will settle out, and you'll have, ex US, being a meaningful part of. everything will settle out and you'll have ex us being a meaningful part of

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...a launch. ...a launch. ...a launch

Speaker 4: Okay. Okay. okay

Speaker 1: There's still a lot of detail that's gotta get worked out between, now and then. There's still a lot of detail that's gotta get worked out between, now and then. there's still a lot of detail that's gotta get worked out between now and then

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: We don't have an answer yet because we're just going through these processes now. As we get more information, we'll be able to read out. I mean, we made the decision to launch, full launch in. We don't have an answer yet because we're just going through these processes now. we don't have an answer yet because we're just going through these processes now As we get more information, we'll be able to read out. as we get more information we'll be able to read out I mean, we made the decision to launch, full launch in. i mean we made the decision to launch full launch in

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...uh, Germany- ...uh, Germany- ...uh germany-

Speaker 4: Yep Yep yep

Speaker 1: ...which started last year. We haven't built out in any other country yet. ...which started last year. ...which started last year We haven't built out in any other country yet. we haven't built out in any other country yet

Speaker 4: Right. Right. right

Speaker 1: It'll be dependent upon the HTA discussions. The good news is, as you know, we're starting from a cost-effective place. When you look at ICER's assessment of Rezdiffra in the U.S., we were considered cost-effective. It'll be dependent upon the HTA discussions. it'll be dependent upon the hta discussions The good news is, as you know, we're starting from a cost-effective place. the good news is as you know we're starting from a cost-effective place When you look at ICER's assessment of Rezdiffra in the U.S., we were considered cost-effective. when you look at icer's assessment of rezdiffra in the u.s we were considered cost-effective

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: Two years later, they did another assessment, and they put us in the high-value category, which meant that it was fairly priced and of significant value to patients and society. That's a great platform to start from when we go to Europe. With Europe, you know, the price that we are offering, the European countries is a blended U.S. government. Two years later, they did another assessment, and they put us in the high-value category, which meant that it was fairly priced and of significant value to patients and society. two years later they did another assessment and they put us in the high-value category which meant that it was fairly priced and of significant value to patients and society That's a great platform to start from when we go to Europe. that's a great platform to start from when we go to europe With Europe, you know, the price that we are offering, the European countries is a blended U.S. government. with europe you know the price that we are offering the european countries is a blended u.s government

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 1: ...price, and that's something which is just not what they're used to seeing. ...price, and that's something which is just not what they're used to seeing. ...price and that's something which is just not what they're used to seeing

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: We're in those discussions. We're hopeful that we will be successful through them. We're in those discussions. we're in those discussions We're hopeful that we will be successful through them. we're hopeful that we will be successful through them

Speaker 4: something more along, around the lines of that 23% discount versus the 30%. something more along, around the lines of that 23% discount versus the 30%. something more along around the lines of that 23% discount versus the 30%

Speaker 1: It's- It's- it's-

Speaker 4: plus that my models usually reflect. plus that my models usually reflect. plus that my models usually reflect

Speaker 1: The price is about, $39,500. The price is about, $39,500. the price is about $39,500

Speaker 4: Okay. Okay. okay

Speaker 1: Okay. Okay. okay

Speaker 4: Got it. Let's. Japan. Just a minute on Japan. Got it. got it Let's. let's Japan. japan Just a minute on Japan. just a minute on japan

Speaker 1: Yeah. Yeah. yeah

Speaker 4: Is Japan different, or is it part of this whole discussion? Is Japan different, or is it part of this whole discussion? is japan different or is it part of this whole discussion

Speaker 1: Japan's on the list as well. Japan's on the list as well. japan's on the list as well

Speaker 4: Okay. Okay. okay

Speaker 1: of countries that, we'd like to pursue- of countries that, we'd like to pursue- of countries that we'd like to pursue-

Speaker 4: Yeah. Yeah. yeah

Speaker 1: approval in. approval in. approval in

Speaker 4: Okay. F4. This is probably gonna be the first phase III F4 MASH trial to read out. What magnitude of effect would you consider clinically meaningful for regulators in commercial success? Not just, like, a statistically significant reduction in events, but, like, when does that start to make sense for clinicians? When does it start to make sense for payers? Okay. okay F4. f4 This is probably gonna be the first phase III F4 MASH trial to read out. this is probably gonna be the first phase iii f4 mash trial to read out What magnitude of effect would you consider clinically meaningful for regulators in commercial success? what magnitude of effect would you consider clinically meaningful for regulators in commercial success Not just, like, a statistically significant reduction in events, but, like, when does that start to make sense for clinicians? not just like a statistically significant reduction in events but like when does that start to make sense for clinicians When does it start to make sense for payers? when does it start to make sense for payers

Speaker 2: I mean, I think you've sort of answered your own question, right? It will be the first trial to read out in F4C. This is an incredibly high unmet need population. I think the answer is it's really something that achieves statistical significance and is approvable. I mean, I think you've sort of answered your own question, right? i mean i think you've sort of answered your own question right It will be the first trial to read out in F4C. it will be the first trial to read out in f4c This is an incredibly high unmet need population. this is an incredibly high unmet need population I think the answer is it's really something that achieves statistical significance and is approvable. i think the answer is it's really something that achieves statistical significance and is approvable

Speaker 4: Anything. Yeah. Anything. anything Yeah. yeah

Speaker 2: Can get to patients. Absolutely. Can get to patients. can get to patients Absolutely. absolutely

Speaker 4: What's the powering on that then? The powering- What's the powering on that then? what's the powering on that then The powering- the powering-

Speaker 2: We haven't talked a lot about the details of the powering of the trial. I can give you some of the... We haven't talked a lot about the details of the powering of the trial. we haven't talked a lot about the details of the powering of the trial I can give you some of the... i can give you some of the

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: -sort of parameters that we've talked about. -sort of parameters that we've talked about. -sort of parameters that we've talked about

Speaker 4: Yeah. Yeah. yeah

Speaker 2: In general, when you look at the F4C population, you know, it's a pretty heterogeneous group. You have people who've just recently transitioned from F3 into cirrhosis. In general, when you look at the F4C population, you know, it's a pretty heterogeneous group. in general when you look at the f4c population you know it's a pretty heterogeneous group You have people who've just recently transitioned from F3 into cirrhosis. you have people who've just recently transitioned from f3 into cirrhosis

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: You've got people who are right on the cusp of decompensation, and they're the ones who have clinically significant portal hypertension. You've got people who are right on the cusp of decompensation, and they're the ones who have clinically significant portal hypertension. you've got people who are right on the cusp of decompensation and they're the ones who have clinically significant portal hypertension

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: Haven't yet had an event, right? Haven't yet had an event, right? haven't yet had an event right

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: One of the important things is making sure you have an enriched population for that latter group to make sure you've got enough people in the study who are gonna be on the cusp of having those events. One of the important things is making sure you have an enriched population for that latter group to make sure you've got enough people in the study who are gonna be on the cusp of having those events. one of the important things is making sure you have an enriched population for that latter group to make sure you've got enough people in the study who are gonna be on the cusp of having those events

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: You can measure an effect size. Based on that enrichment, we expect a placebo event rate somewhere in the 5%-10% range. There's some publications out there where, you know, there are some high-level assessments of powering and study design, which are in the general range. You can measure an effect size. you can measure an effect size Based on that enrichment, we expect a placebo event rate somewhere in the 5%-10% range. based on that enrichment we expect a placebo event rate somewhere in the 5%-10% range There's some publications out there where, you know, there are some high-level assessments of powering and study design, which are in the general range. there's some publications out there where you know there are some high-level assessments of powering and study design which are in the general range

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: -of, an effect size of 50% to 35%. -of, an effect size of 50% to 35%. -of an effect size of 50% to 35%

Speaker 4: How sure are you, based on prior data, that these patients aren't too relentlessly on their march towards decompensation that you can't pull them back? How sure are you, based on prior data, that these patients aren't too relentlessly on their march towards decompensation that you can't pull them back? how sure are you based on prior data that these patients aren't too relentlessly on their march towards decompensation that you can't pull them back

Speaker 2: I'm so glad you asked that question. This is where the 122 patient open label. I'm so glad you asked that question. i'm so glad you asked that question This is where the 122 patient open label. this is where the 122 patient open label

Speaker 4: Yeah. Yeah. yeah

Speaker 2: really tells us some really important information. Okay. so we had a cohort of F4C patients, in one of the earlier studies. really tells us some really important information. really tells us some really important information Okay. so we had a cohort of F4C patients, in one of the earlier studies. okay so we had a cohort of f4c patients in one of the earlier studies

Speaker 4: Mm-hmm. Yep. Mm-hmm. mm-hmm Yep. yep

Speaker 2: exposed to resmetirom now for two years, and we showed these data last year. Again, very similar baseline characteristics as the people enrolled in the MAESTRO outcomes randomized trial. exposed to resmetirom now for two years, and we showed these data last year. exposed to resmetirom now for two years and we showed these data last year Again, very similar baseline characteristics as the people enrolled in the MAESTRO outcomes randomized trial. again very similar baseline characteristics as the people enrolled in the maestro outcomes randomized trial

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: A lot of those patients with clinically significant portal hypertension. A lot of those patients with clinically significant portal hypertension. a lot of those patients with clinically significant portal hypertension

Speaker 4: Right. The CSPC. Right. right The CSPC. the cspc

Speaker 2: Yeah. The ones right on the cusp of decompensation. What we see in that population is a shift towards lower portal hypertension risk scores called. Yeah. yeah The ones right on the cusp of decompensation. the ones right on the cusp of decompensation What we see in that population is a shift towards lower portal hypertension risk scores called. what we see in that population is a shift towards lower portal hypertension risk scores called

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: Baveno classification. Even in the sickest patients and the people already with clinically significant portal hypertension, we can shift those people into lower classifications of clinically significant portal hypertension. Baveno classification. baveno classification Even in the sickest patients and the people already with clinically significant portal hypertension, we can shift those people into lower classifications of clinically significant portal hypertension. even in the sickest patients and the people already with clinically significant portal hypertension we can shift those people into lower classifications of clinically significant portal hypertension

Speaker 4: You feel that between the Baveno and the portal hypertension, that's the best proxy for events? You feel that between the Baveno and the portal hypertension, that's the best proxy for events? you feel that between the baveno and the portal hypertension that's the best proxy for events

Speaker 2: Yeah. The Baveno criteria and clinically significant portal hypertension are very good predictors of liver-related events. Yeah. yeah The Baveno criteria and clinically significant portal hypertension are very good predictors of liver-related events. the baveno criteria and clinically significant portal hypertension are very good predictors of liver-related events

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: Right? Right? right

Speaker 4: If you can hold them back on that, they're savable. If you can hold them back on that, they're savable. if you can hold them back on that they're savable

Speaker 2: Correct. Exactly. Correct. correct Exactly. exactly

Speaker 4: Got it. Oh, I lost my space. Got it. got it Oh, I lost my space. oh i lost my space

Speaker 2: Well, I'll just add that. Well, I'll just add that. well i'll just add that

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: there are other data. We looked at clinically significant portal hypertension, and that sort of classification shift, but we also saw important changes in other biomarkers like. there are other data. there are other data We looked at clinically significant portal hypertension, and that sort of classification shift, but we also saw important changes in other biomarkers like. we looked at clinically significant portal hypertension and that sort of classification shift but we also saw important changes in other biomarkers like

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: MRE, MR elastography, and liver function tests that also sort of, you know, trended in the right direction. MRE, MR elastography, and liver function tests that also sort of, you know, trended in the right direction. mre mr elastography and liver function tests that also sort of you know trended in the right direction

Speaker 4: Can you review what the main operational risks are to the timeline for 2027 data? I think that's been... A big fear is that... Can you review what the main operational risks are to the timeline for 2027 data? can you review what the main operational risks are to the timeline for 2027 data I think that's been... i think that's been A big fear is that... a big fear is that

Speaker 2: For the outcome study. For the outcome study. for the outcome study

Speaker 4: For the outcome study. Yeah. For the outcome study. for the outcome study Yeah. yeah

Speaker 2: Yeah. Yeah. yeah

Speaker 4: You're gonna have 2027 data, and they're gonna open up the envelope you're gonna be underpowered. You're gonna have 2027 data, and they're gonna open up the envelope you're gonna be underpowered. you're gonna have 2027 data and they're gonna open up the envelope you're gonna be underpowered

Speaker 1: Well, yeah. I mean, look, it's an event-driven trial, right? Well, yeah. well yeah I mean, look, it's an event-driven trial, right? i mean look it's an event-driven trial right

Speaker 4: if you need. if you need. if you need

Speaker 1: When we have enough events, I mean, look, we're not gonna. December 31st isn't gonna come, and if we haven't had enough events, we're gonna say it, the study's over. We're gonna make sure that we have enough events. When we have enough events, I mean, look, we're not gonna. when we have enough events i mean look we're not gonna December 31st isn't gonna come, and if we haven't had enough events, we're gonna say it, the study's over. december 31st isn't gonna come and if we haven't had enough events we're gonna say it the study's over We're gonna make sure that we have enough events. we're gonna make sure that we have enough events

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: It is tracking towards- It is tracking towards- it is tracking towards-

Speaker 4: You're tracking towards enough events. You're tracking towards enough events. you're tracking towards enough events

Speaker 1: 27, we're gonna be pragmatic and see what happens. 27, we're gonna be pragmatic and see what happens. 27 we're gonna be pragmatic and see what happens

Speaker 4: Understood. Understood. understood

Speaker 1: Is that- Is that- is that-

Speaker 2: Yeah. Yeah. yeah

Speaker 1: Is that a fair- Is that a fair- is that a fair-

Speaker 2: Exactly. Exactly. exactly

Speaker 1: Okay. Okay. okay

Speaker 2: I think with respect to, you know, like any outcomes trial, the key is retaining patients in the study, and we've done, I think, a great job at keeping patients in this study. As Bill said, it's really about getting to that target number of events. I think with respect to, you know, like any outcomes trial, the key is retaining patients in the study, and we've done, I think, a great job at keeping patients in this study. i think with respect to you know like any outcomes trial the key is retaining patients in the study and we've done i think a great job at keeping patients in this study As Bill said, it's really about getting to that target number of events. as bill said it's really about getting to that target number of events

Speaker 4: How do you see positive or negative outcome study from this trial impacting whether it's Rezdiffra's label expansion, potentially destabilizing the accelerator approval or market opportunity revenue trajectory? Yep. How do you see positive or negative outcome study from this trial impacting whether it's Rezdiffra's label expansion, potentially destabilizing the accelerator approval or market opportunity revenue trajectory? how do you see positive or negative outcome study from this trial impacting whether it's rezdiffra's label expansion potentially destabilizing the accelerator approval or market opportunity revenue trajectory Yep. yep

Speaker 1: Well, look, we've talked about this being a potential doubling of the opportunity. Fewer patients. There's about 235,000 F4C patients. This was when we read it out in 2013. Fewer patients, but higher unmet needs, we would expect- Well, look, we've talked about this being a potential doubling of the opportunity. well look we've talked about this being a potential doubling of the opportunity Fewer patients. fewer patients There's about 235 ,000 F4C patients. there's about 235 ,000 f4c patients This was when we read it out in 2013. this was when we read it out in 2013 Fewer patients, but higher unmet needs, we would expect- fewer patients but higher unmet needs we would expect-

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: increased penetration into that faster. It's a great opportunity for us. I think it also has a carry-through to F2, F3, where people will see, well, if it's working in F4C, another reason to believe in F2, F3. increased penetration into that faster. increased penetration into that faster It's a great opportunity for us. it's a great opportunity for us I think it also has a carry-through to F2, F3, where people will see, well, if it's working in F4C, another reason to believe in F2, F3. i think it also has a carry-through to f2 f3 where people will see well if it's working in f4c another reason to believe in f2 f3

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 1: I think that, what we have, and, you know, nobody else has this, we already have, you know, over 36,000 patients on drug. By the time we read out and the time we get approval, we're gonna have that much more in our denominator, just that much more experience and certainty about the profile of the brand for when you start to write for F4C. I think that, what we have, and, you know, nobody else has this, we already have, you know, over 36,000 patients on drug. i think that what we have and you know nobody else has this we already have you know over 36,000 patients on drug By the time we read out and the time we get approval, we're gonna have that much more in our denominator, just that much more experience and certainty about the profile of the brand for when you start to write for F4C. by the time we read out and the time we get approval we're gonna have that much more in our denominator just that much more experience and certainty about the profile of the brand for when you start to write for f4c

Speaker 4: I have left... Oh, go ahead. I have left... i have left Oh, go ahead. oh go ahead

Speaker 2: I was just gonna add that the, you know, a positive F4C study opens the F4C indication itself, plus it gives us full approval on F2, F3. Right. I was just gonna add that the, you know, a positive F4C study opens the F4C indication itself, plus it gives us full approval on F2, F3. i was just gonna add that the you know a positive f4c study opens the f4c indication itself plus it gives us full approval on f2 f3 Right. right

Speaker 4: All right. I have left myself 5 minutes to go over your oral GLP-1 ERVO and the siRNA programs. Dave, which one should I start with? All right. all right I have left myself 5 minutes to go over your oral GLP-1 ERVO and the siRNA programs. i have left myself 5 minutes to go over your oral glp-1 ervo and the sirna programs Dave, which one should I start with? dave which one should i start with

Speaker 2: I would start with ERVO. I would start with ERVO. i would start with ervo

Speaker 4: Okay, let's start with ERVO. How are you approaching the combo dose selection, and what's the most important measurement when you're evaluating dose selection? Okay, let's start with ERVO. okay let's start with ervo How are you approaching the combo dose selection, and what's the most important measurement when you're evaluating dose selection? how are you approaching the combo dose selection and what's the most important measurement when you're evaluating dose selection

Speaker 2: Yeah. I mean, just for a bit of background. Yeah. yeah I mean, just for a bit of background. i mean just for a bit of background

Speaker 4: Yeah. Yeah. yeah

Speaker 2: ervogastat's a DGAT2 inhibitor that we recently licensed in from Pfizer. It had actually been through a phase II development program, so we know a lot about this drug already. And including the dose range. ervogastat's a DGAT2 inhibitor that we recently licensed in from Pfizer. ervogastat's a dgat2 inhibitor that we recently licensed in from pfizer It had actually been through a phase II development program, so we know a lot about this drug already. it had actually been through a phase ii development program so we know a lot about this drug already And including the dose range. and including the dose range

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 2: ... which helps us a lot. ... which helps us a lot. which helps us a lot

Speaker 4: They've sorted through, they... Pfizer- They've sorted through, they... they've sorted through they Pfizer- pfizer-

Speaker 2: Yeah Yeah yeah

Speaker 4: ... went through? Okay. ... went through? went through Okay. okay

Speaker 2: They had some- They had some- they had some-

Speaker 4: All right. All right. all right

Speaker 2: They had dose ranging. They had dose ranging. they had dose ranging

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 2: ... data in their phase II program. ... data in their phase II program. data in their phase ii program

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: That helps us a lot and some of the measures that they used are the same that we've used with resmetirom, for example, MRI-PDFF, which is reduction of fat content in the liver, and we see ervogastat's a very strong reducer of hepatic fat. Why, why is that important? That's important because there's a strong relationship between resmetirom's reduction of PDFF and improvement in fibrosis. The concept here is because of the two complementary mechanisms of action of these two drugs, we'll be able to get more fat reduction out of the liver, push more patients into that high responder range, and get better anti-fibrotic efficacy- That helps us a lot and some of the measures that they used are the same that we've used with resmetirom, for example, MRI-PDFF, which is reduction of fat content in the liver, and we see ervogastat's a very strong reducer of hepatic fat. that helps us a lot and some of the measures that they used are the same that we've used with resmetirom for example mri-pdff which is reduction of fat content in the liver and we see ervogastat's a very strong reducer of hepatic fat Why, why is that important? why why is that important That's important because there's a strong relationship between resmetirom's reduction of PDFF and improvement in fibrosis. that's important because there's a strong relationship between resmetirom's reduction of pdff and improvement in fibrosis The concept here is because of the two complementary mechanisms of action of these two drugs, we'll be able to get more fat reduction out of the liver, push more patients into that high responder range, and get better anti-fibrotic efficacy- the concept here is because of the two complementary mechanisms of action of these two drugs we'll be able to get more fat reduction out of the liver push more patients into that high responder range and get better anti-fibrotic efficacy-

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 2: with the combination. That's essentially the idea behind it. with the combination. with the combination That's essentially the idea behind it. that's essentially the idea behind it

Speaker 4: timelines. timelines. timelines

Speaker 2: Uh- Uh- uh-

Speaker 4: ... for the ERVO program right now? ... for the ERVO program right now? for the ervo program right now

Speaker 2: Yeah. You know, all the time, you know, when you in-license a program, there's a little bit of block and blocking and tackling, updating regulatory documents, all that kind of stuff. We'll conduct a drug-drug interaction study with resmetirom and ervogastat later this year, go to the FDA, talk about combination drug development studies in phase II. Yeah. yeah You know, all the time, you know, when you in-license a program, there's a little bit of block and blocking and tackling, updating regulatory documents, all that kind of stuff. you know all the time you know when you in-license a program there's a little bit of block and blocking and tackling updating regulatory documents all that kind of stuff We'll conduct a drug-drug interaction study with resmetirom and ervogastat later this year, go to the FDA, talk about combination drug development studies in phase II. we'll conduct a drug-drug interaction study with resmetirom and ervogastat later this year go to the fda talk about combination drug development studies in phase ii

Speaker 4: Interesting Interesting interesting

Speaker 2: And do that in 2027. And do that in 2027. and do that in 2027

Speaker 4: 2027, like a factorial start? 2027, like a factorial start? 2027 like a factorial start

Speaker 2: something like that, yeah. something like that, yeah. something like that yeah

Speaker 4: Something like that. Got it. Something like that. something like that Got it. got it

Speaker 2: Yeah. Yeah. yeah

Speaker 4: MGL-2086, this is your oral GLP-1. Remind us what scaffold that is and how it differentiates from existing GLP-1s in terms of efficacy, safety, convenience. MGL-2086, this is your oral GLP-1. mgl-2086 this is your oral glp-1 Remind us what scaffold that is and how it differentiates from existing GLP-1s in terms of efficacy, safety, convenience. remind us what scaffold that is and how it differentiates from existing glp-1s in terms of efficacy safety convenience

Speaker 2: Yeah. It's on the orforglipron scaffold. Yeah. yeah It's on the orforglipron scaffold. it's on the orforglipron scaffold

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: That's... There are a few things that were attractive about the product. It's on the orforglipron scaffold. The preclinical data were all done by CSPC, our partner in China. Actually, they compared an to orforglipron in a lot of the studies, so we can get a good sense of the relative efficacy of the study, preclinically at least. That's... that's There are a few things that were attractive about the product. there are a few things that were attractive about the product It's on the orforglipron scaffold. it's on the orforglipron scaffold The preclinical data were all done by CSPC, our partner in China. the preclinical data were all done by cspc our partner in china Actually, they compared an to orforglipron in a lot of the studies, so we can get a good sense of the relative efficacy of the study, preclinically at least. actually they compared an to orforglipron in a lot of the studies so we can get a good sense of the relative efficacy of the study preclinically at least

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: That sort of de-risks it for us. Then from a chemical standpoint, it looks like it should be combinable with resmetirom into a fixed-dose combination. That sort of de-risks it for us. that sort of de-risks it for us Then from a chemical standpoint, it looks like it should be combinable with resmetirom into a fixed-dose combination. then from a chemical standpoint it looks like it should be combinable with resmetirom into a fixed-dose combination

Speaker 4: In, like, a co-formulation tablet kind of thing? In, like, a co-formulation tablet kind of thing? in like a co-formulation tablet kind of thing

Speaker 2: That would be the idea. That would be the idea. that would be the idea

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: Yeah, exactly. I think for a lot of reasons, 2086 was a great opportunity. Yeah, exactly. yeah exactly I think for a lot of reasons, 2086 was a great opportunity. i think for a lot of reasons 2086 was a great opportunity

Speaker 4: Mm-hmm Mm-hmm mm-hmm

Speaker 2: for us and looks like it could be a great combination product for us. for us and looks like it could be a great combination product for us. for us and looks like it could be a great combination product for us

Speaker 4: MGL-2086, that's going to go into phase I as a monotherapy. MGL-2086, that's going to go into phase I as a monotherapy. mgl-2086 that's going to go into phase i as a monotherapy

Speaker 2: Yes Yes yes

Speaker 4: this year? this year? this year

Speaker 2: So- So- so-

Speaker 4: Okay. 2027 Okay. 2027 okay 2027

Speaker 2: Yeah Yeah yeah

Speaker 4: ... we'll start talking about combinations. ... we'll start talking about combinations. we'll start talking about combinations

Speaker 2: The usual sort of early phase drug development stuff to start with. The usual sort of early phase drug development stuff to start with. the usual sort of early phase drug development stuff to start with

Speaker 4: Your GalNAc conjugated siRNAs in the last minute or so, how are you going to prioritize which targets to advance into clinical development, when could we expect, like, preclinical data? Because, you know, with RNA mechanisms, preclinical, especially non-human primate data, can be particularly meaningful. Your GalNAc conjugated siRNAs in the last minute or so, how are you going to prioritize which targets to advance into clinical development, when could we expect, like, preclinical data? your galnac conjugated sirnas in the last minute or so how are you going to prioritize which targets to advance into clinical development when could we expect like preclinical data Because, you know, with RNA mechanisms, preclinical, especially non-human primate data, can be particularly meaningful. because you know with rna mechanisms preclinical especially non-human primate data can be particularly meaningful

Speaker 2: Yeah, I mean, first of all, it was a great opportunity to work with Ribocure. They're a company based in Gothenburg and also in China. A lot of, you know, really great experience with siRNA technology, and, you know, a great team over there. What we've talked about is we've done a deal on six targets. Yeah, I mean, first of all, it was a great opportunity to work with Ribocure. yeah i mean first of all it was a great opportunity to work with ribocure They're a company based in Gothenburg and also in China. they're a company based in gothenburg and also in china A lot of, you know, really great experience with siRNA technology, and, you know, a great team over there. a lot of you know really great experience with sirna technology and you know a great team over there What we've talked about is we've done a deal on six targets. what we've talked about is we've done a deal on six targets

Speaker 4: Mm-hmm. Mm-hmm. mm-hmm

Speaker 2: We haven't been specific about the targets yet. All of them are early. They're all preclinical, at this phase, so it's a bit premature for us to talk about exactly what the targets are. As we get more data and we have more to share, we'll of course update on that. We haven't been specific about the targets yet. we haven't been specific about the targets yet All of them are early. all of them are early They're all preclinical, at this phase, so it's a bit premature for us to talk about exactly what the targets are. they're all preclinical at this phase so it's a bit premature for us to talk about exactly what the targets are As we get more data and we have more to share, we'll of course update on that. as we get more data and we have more to share we'll of course update on that

Speaker 4: Don't expect preclinical data in 2026 or anytime? Don't expect preclinical data in 2026 or anytime? don't expect preclinical data in 2026 or anytime

Speaker 2: TBD. TBD. tbd

Speaker 4: TBD. great. With that, we are at time. Thank you, guys. Thanks, Victor. TBD. great. tbd great With that, we are at time. with that we are at time Thank you, guys. thank you guys Thanks, Victor. thanks victor

Speaker 2: Thank you, Rachel. Thank you, Rachel. thank you rachel

Speaker 4: Thank you for the insight. Thank you for the insight. thank you for the insight